Epstein-Barr virus (EBV), an oncogenic herpesvirus, is unique in its capacity to infect selectively and immortalize B lymphocytes from humans and some primates. Clinically, EBV infects over 90% of humans by adulthood, and subsequently is maintained in a latent state within peripheral B lymphocytes. However, during states of impaired immune surveillance such as acquired immunodeficiency syndrome, post-transplant immunosuppression, and malaria, these lymphocytes are transformed into B cell malignancies such as Burkitt's lymphoma. The narrow tropism of EBV is a unique area of investigation for several reasons. First, EBV is the only herpesvirus with a single predominant membrane glycoprotein, and the only herpesvirus for which the viral ligand and its host receptor have been defined biochemically. It is this envelope glycoprotein, gp350/220, that contains the amino terminal sequence EDPGFFNVE which has been shown to be the primary binding site for EBV on human complement receptor type 2 (CR2), and corresponds to the sequence EDPGKQLYNVE of human C3dg, the natural ligand for CR2. Second, while poliovirus, rhinovirus, and HIV exploit receptors of the Ig superfamily, EBV, through its specific interaction with CR2, is the only virus known to gain intracellular access through a member of the family of proteins that contain short consensus repeats (SCRs). Third, murine CR2 is the only known example of a viral receptor homologue that binds the heterologous natural ligand but not the virus. It has never been possible to study structural domains of human CR2 required for infection of B lymphocytes or B lymphoblastoid cell lines with EBV because all such cells express wildtype CR2. However, we have recently determined the structural basis for selective binding of EBV to human CR2 expressed on non-B cells. These observations, as will be described, have now led to the development of two novel experimental systems for study of both the role of CR2 during EBV infection of B lymphocytes as well as structure-function relationships among SCR- containing proteins in general.